PROJECT SUMMARY Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related condition in which hematopoietic stem cells in the bone marrow undergo somatic mutations that lead to overgrowth (?clones?) of a genetically distinct subpopulation of blood cells. Evidence is mounting that CHIP has major implications for human health as a risk factor for mortality and chronic diseases including hematologic cancers and atherosclerotic cardiovascular disease (CVD). Prior studies of CHIP were cross-sectional and limited information is available on behavioral/lifestyle, environmental, and heritable risk factors for the development, progression, and the occurrence of CHIP and also the relationship of CHIP to risk of specific CVD subtypes (coronary heart disease, stroke, and venous thromboembolic disease), pre-malignant blood diseases, and dementia over long- term follow up. The large (N~161,000), multi-ethnic, prospective Women?s Health Initiative (WHI), which enrolled post-menopausal women during 1993-1998 is particularly well-suited to address these limitations because of its longitudinal design, availability of extensive exposure and phenotype data, and ongoing surveillance of incident disease/mortality among aging women. In particular, a subset of ~7,800 of the original WHI cohort underwent a subsequent examination and blood sampling in 2012 (ranging from 14 to 19 years after WHI enrollment) as part of the WHI Long Life Study (LLS). Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) Project, 11,000 original WHI participants (including approximately 1,400 WHI-LLS participants) have undergone deep- coverage (30x) whole genome sequencing of their baseline genomic DNA and are currently undergoing somatic variant genotype calling for assessment of CHIP. Through the current R01 proposal, we will additionally perform CHIP genotyping and detection by targeted hematopoiesis gene sequencing in the remaining 6,400 WHI-LLS samples (at baseline) and the full set of 7,800 WHI-LLS participants using peripheral blood genomic DNA extracted at the LLS exam. In Aim 1, we will estimate associations between prevalent CHIP (at baseline), incidence or progression of CHIP (between baseline and LLS), and putative socio-demographic, cardiometabolic, behavioral, pharmacologic, environmental, genetic, and aging-related risk factors for CHIP. In Aim 2, we will estimate CHIP-outcome associations using the LLS cohort and TOPMed baseline CHIP data (total N=17,000) with incident clinical cardiovascular, hematologic, neurocognitive, and mortality outcomes. In Aim 3, informed by results from Aims 1 and 2, we will use Mendelian randomization approaches, mediation analyses, and polygenic risk scores to assess causal mediation of exposure-outcome associations by CHIP and the mechanisms by which heritable germline variants contribute to CHIP.